A Bayesian phase 2 model based adaptive design to optimise antivenom dosing: Application to a dose-finding trial for a novel Russell's viper antivenom in Myanmar.

Autor: Watson JA; Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.; Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom., Lamb T; Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.; Myanmar-Oxford Clinical Research Unit, Yangon, Myanmar., Holmes J; Centre for Statistics in Medicine, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom., Warrell DA; Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom., Thwin KT; University of Medicine 1, Yangon, Myanmar., Aung ZL; University of Medicine 1, Yangon, Myanmar., Oo MZ; University of Medicine 2, Yangon, Myanmar., Nwe MT; Myanmar-Oxford Clinical Research Unit, Yangon, Myanmar., Smithuis F; Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.; Myanmar-Oxford Clinical Research Unit, Yangon, Myanmar., Ashley EA; Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.; Myanmar-Oxford Clinical Research Unit, Yangon, Myanmar.; Lao-Oxford-Mahosot Hospital Wellcome Trust Research Unit, Vientiane, Laos.
Jazyk: angličtina
Zdroj: PLoS neglected tropical diseases [PLoS Negl Trop Dis] 2020 Nov 16; Vol. 14 (11), pp. e0008109. Date of Electronic Publication: 2020 Nov 16 (Print Publication: 2020).
DOI: 10.1371/journal.pntd.0008109
Abstrakt: For most antivenoms there is little information from clinical studies to infer the relationship between dose and efficacy or dose and toxicity. Antivenom dose-finding studies usually recruit too few patients (e.g. fewer than 20) relative to clinically significant event rates (e.g. 5%). Model based adaptive dose-finding studies make efficient use of accrued patient data by using information across dosing levels, and converge rapidly to the contextually defined 'optimal dose'. Adequate sample sizes for adaptive dose-finding trials can be determined by simulation. We propose a model based, Bayesian phase 2 type, adaptive clinical trial design for the characterisation of optimal initial antivenom doses in contexts where both efficacy and toxicity are measured as binary endpoints. This design is illustrated in the context of dose-finding for Daboia siamensis (Eastern Russell's viper) envenoming in Myanmar. The design formalises the optimal initial dose of antivenom as the dose closest to that giving a pre-specified desired efficacy, but resulting in less than a pre-specified maximum toxicity. For Daboia siamensis envenoming, efficacy is defined as the restoration of blood coagulability within six hours, and toxicity is defined as anaphylaxis. Comprehensive simulation studies compared the expected behaviour of the model based design to a simpler rule based design (a modified '3+3' design). The model based design can identify an optimal dose after fewer patients relative to the rule based design. Open source code for the simulations is made available in order to determine adequate sample sizes for future adaptive snakebite trials. Antivenom dose-finding trials would benefit from using standard model based adaptive designs. Dose-finding trials where rare events (e.g. 5% occurrence) are of clinical importance necessitate larger sample sizes than current practice. We will apply the model based design to determine a safe and efficacious dose for a novel lyophilised antivenom to treat Daboia siamensis envenoming in Myanmar.
Competing Interests: The authors have declared that no competing interests exist.
Databáze: MEDLINE
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